Epidemiologic studies strongly support a genetic basis for susceptibility to human SLE, and genetically-defined murine models of systemic lupus indicate that lupus is a complex, polygenic disease with a threshold liability for inheritance. These studies in "lupus-like" mice suggest that different genes may control different aspects of the autoimmune phenotype. Most importantly, these studies, coupled with the rapid advances in knowledge available through the human genome project, underscore the feasibility of using the tools of modem genetics in defining human disease susceptibility and severity. The approach to the genetics of human SLE requires a multidisciplinary, team effort. Within this Program Project, we have assembled a unique and exceptionally strong multidisciplinary team, which leverages both fundamental and clinical investigations in SLE at the host institution and at the partner institutions. Our team expertise includes mastery of the theory and techniques of modem genetic mapping (linkage and association), full appreciation of the SLE clinical phenotypes and the proven ability to recruit and maintain cohorts of SLE patients (multiplex families, simplex families, case-control and longitudinal cohorts). Uniting this expertise is a broad appreciation for the pathophysiological processes in SLE in order to facilitate the selection of candidate genes and to translate findings into meaningful, mechanism-based clinical intervention. Through our team effort, we have an unprecedented power to accelerate the pace of discovery, to replicate and narrow regions of linkage, to pursue the structure and biology of candidate genes, and to test the relevance of these discoveries to clinical phenotype in a very large, meticulously studied cohort of SLE patients. Our efforts will advance our understanding of SLE and leverage both the application of current therapy and the development of new, mechanism-based therapies.